The invention relates generally to botanical extracts and, more specifically, to extracts of passion fruit (Passiflora sp.), including particularly extracts of the skin of passion fruit, and the use of the extracts for food, nutraceutical, and medical applications.
Hypertension, or a blood pressure higher than 140/90 mm Hg, is the most common risk factor for cardiovascular and cerebrovascular morbidity and mortality. In the United States, high blood pressure is responsible for 40,000 deaths annually, while being the most modifiable risk factor for stroke. Hypertension affects about one in four adults, or almost 50 million people in the United States.
A Framingham study showed that as people aged from 30 to 65 years, their blood pressure increased an average 20 mm Hg systolic and 10 mm Hg diastolic pressure, with systolic blood pressure continuing to rise up to age 90.
While higher blood pressure increases the likelihood of a cardiovascular event, hypertension is not often well controlled and too few patients are adequately treated. Epidemiologic studies predict that reduction of the systemic blood pressure by the amount usually achieved in major clinical trials could reduce cerebrovascular events by 42% and cardiac events by 24%
Hypertension is frequently treated non-specifically, resulting in a large number of minor side effects, and a relatively high rate of non- or inadequate treatment. Thus, the search for new treatments for hypertension remains ongoing.
Therapies derived from natural products are well known. It has been established that certain flavonoids have a beneficial effect on hypertension. For example, a bark extract from the French maritime pine (Pinus pinaster), which contains a mixture of flavonoids, decreases systolic blood pressure when taken orally by mildly hypertensive patients.
Nitric oxide is an important molecular regulator of blood pressure. Nitric oxide is a potent vasodilator. It inhibits platelet activation, limits leukocyte adhesion to the endothelium, and regulates myocardiocontractility. Synthesis of nitric oxide catalyzed by nitric oxide synthase (NOS) occurs in the vascular endothelium while the production of nitric oxide involving inducible nitric oxide synthase (iNOS) is associated with immune function. However, small amounts of nitric oxide produced by another NOS, epithelial nitric oxide synthase (eNOS), have a cytoprotective effect and vasodilation action on the cardiovascular system.
Peroxynitrite is a potentially damaging oxidant, formed from nitric oxide (NO+O2ONOO). Peroxynitrite can give rise to lipid peroxidation, protein nitration, DNA single-strand breakage, and guanidine nitration.
It has been shown that the flavonoids quercetin and kaempferol inhibit NOLA-dependent spontaneous aortic ring contraction in spontaneously hypertensive rat (SHR) cells in vitro. NOLA is a nitric oxide synthase inhibitor. Large dose acetylcholine-induced vascular contraction can also be inhibited by antioxidative flavonoids such as quercetin, kaempferol, rutin, and esculetin. Inhibition of vascular smooth muscle contraction should lead to lower blood pressure.
In addition, the effects of flavonoids on immune function are controversial. Catechin enhances proliferation of lymphocytes and antibody production, while it exerts an inhibitory effect at high concentration. Some studies show that flavonoids enhance NK cell activity, while other studies show that flavonoids have no effect. Quercetin seems to inhibit non-specific immunological responses and exerts an anti-inflammatory action.
Asthma is a very common disease, affecting 4-5% of the population of the United States with incidence increasing rapidly. It is recognized as comprising a chronic, eosinophilic bronchitis and mediator-driven inflammatory process in the lungs. These agents produce potent bronchoconstriction, increased endothelial membrane permeability leading to airway edema, and enhanced secretion of thick, viscous mucus (Wenzel S E. Arachidonic acid metabolites: Mediators of inflammation in asthma. Pharmacotherapy 1997; 17(1 Pt2):3S-12S). A widespread narrowing of the air passages manifests asthma. This may be relieved spontaneously or as a result of therapy, and is defined clinically by paroxysms of dyspnea, cough, and wheezing. Asthma is an episodic disease: acute exacerbations are interspersed with symptom-free periods. Oxidants, organic dust, airborne allergens, chemical substances, cold air, and virus infections can trigger asthma attacks. Most attacks are short-lived, lasting minutes to hours, and clinically the patient recovers completely afterwards.
Although asthma is primarily a disease of airways, virtually all aspects of pulmonary function are compromised during an acute attack. When a patient presents for therapy, forced vital capacity (FVC) tends to be less than 50% of normal. The 1-second forced expiratory volume (FEV1) averages 30% or less than that of healthy people, and the maximum and minimum mid-expiratory flow rates are reduced to 20% or less than expected. In acutely ill patients, the residual volume (RV) frequently approaches 400% of normal and functional residual capacity doubles. The patients usually report that the attack has clinically ended when the RV has fallen to 200% of its predicted value and the FEV1 reaches 50% of the predicted value (American Thoracic Society: Lung function testing: Selection of reference values and interpretative strategies. Am Rev Respir Dis 1991; 144:1202-1218).
Asthma diagnosis is established by demonstrating reversible airway obstruction. Reversibility is traditionally defined as a 15% or greater increase in FEV1 after 2 puffs of a β-adrenergic agonist. Once the diagnosis is confirmed, the course of the illness and the effectiveness of therapy can be monitored by measuring peak expiratory flow rate at home or FEV1 in the laboratory or both. Successful asthma treatment is accomplished with the use of a β-agonist for the early stage and reduction of inflammation with anti-inflammatory agents such as glucocorticoids (which decrease airway hyper-responsiveness) for the late stage.
More than 15 million Americans suffer from rheumatoid and osteoarthritis. The most common source of adult disability is due to osteoarthritis of the knee. Studies have documented radiological knee osteoarthritis and symptomatic osteoarthritis in 12% and 6%, respectively, of women aged 45-64. It has also been reported that the age-and-sex standardized incidence rate for knee osteoarthritis is approximately 240 of 100,000 persons per year.
Although osteoarthritis is not considered an inflammatory disease, mediators classically associated with inflammation perpetuate cartilage damage that ensues from repeated mechanical injury. Cartilage destruction, an important pathological feature and a major cause of joint dysfunction, is mediated by two distinct pathways: Intrinsic, in which chondrocytes are responsible for the degradation of the extracellular matrix; and extrinsic, wherein cells and tissues other than chondrocytes, such as inflamed synovium, pannus tissue, and inflammatory cells affect the extra cellular matrix via synovial fluids.
It has been shown that Matrix metalloproteinases (MMPs), major proteolytic enzymes involved in extracellular matrix turnover, are expressed in osteoarthritic cartilage and contribute to tissue damage. Another suspected mediator of tissue damage is overproduction of nitric oxide (NO), a major catabolic factor produced by chondrocytes in response to proinflammatory cytokines such as IL-1β and TNF-α. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly used medications for arthritis, but are associated clinically with significant complications including non-ulcer dyspepsia, symptomatic gastric and duodenal ulcers, ulcer hemorrhages and perforations. Their economic impact includes 100,000 hospitalizations annually, costing $1.6 billion with 17,000 deaths. The complications of NSAIDs have increased with the aging of the American population and heightened use of aspirin for cardioprophylaxis. Accordingly, there is an increasing need to develop effective and safe treatment to minimize the adverse events in patients with osteoarthritis.
Passion fruit (Passiflora edulis) is a subtropical or tropical plant with a vigorous climbing character, growing to 20 ft. The purple passion fruit is native from southern Brazil through Paraguay to northern Argentina. Its fruit is nearly round or ovoid, 1.5 to 3 inches wide, with a tough, smooth and waxy rind.
In a search for bioactive constituents of passion fruit, it has now surprisingly been found that a passion fruit extract has an ameliorating effect on inflammation disorders. Inflammation, particularly chronic inflammation, has been implicated in cancer, hypertension, allergy, diabetes, chronic skin disorders, and autoimmune diseases such as lupus and multiple sclerosis. Passion fruit extract lowers systolic blood pressure in spontaneously hypertensive rats (SHR), and decreases nitric oxide production from iNOS, thus improving endothelial dysfunction in SHR. It is therefore also envisaged that the passion fruit extract will exhibit antioxidant properties. Passion fruit extract decreases the severity of symptoms of asthma, including wheezing, coughing, shortness of breath, and reduced expiratory functions. Passion fruit extract decreases the severity of osteoarthritis, including pain, stiffness and physical function.
It is therefore an object of the invention to provide an extract of passion fruit which exhibits therapeutic effects against hypertension and diseases associated with hypertension, asthma, osteoarthritis, and which is hepatoprotective, or at least to provide a useful choice.